eign antigen only when accompanied by an MHC
antigen; however, the mechanism of this MHC
restriction has not yet been defined. The class III
MHC genes encode components of the complement system and will be discussed in Section 6.6.
The best-characterized MHCs are the murine
H-2 complex and the human HLA complex
[50,87]. The H-2 complex on mouse chromosome 7 extends over 4000 kb. The classical transplantation antigens of class I are encoded in loci
K, D and L. All the genes of this group so far
sequenced contain eight exons corresponding to
the subdivisions of the polypeptide; exon 1 encodes the signal peptide, exons 2-4 encode the
three extracellular domains aI, a2 and a3, exon 5
encodes the transmembrane region and
exons 6-8 code for the small cytoplasmic
domain. The complete polypeptide of 45 kDa,
anchored in the cell membrane, is bound noncovalently via domain a3 to the 12-kDa large
~2microglobulin (~2m). The domain a3 and the
~2m each correspond to one Ig homology unit
(Fig. 6.2). Class I also includes the Oa antigen,
which is found predominantly on Band T lymphocytes, and the Tla antigen, which is found on
the thymocytes; these two molecules are much
more polymorphic than the transplantation antigen and are not involved in the MHC-restricted
recognition by T lymphocytes. In all there are
30-40 class I genes in the mouse, most of which
can be allotted to the Oa and Tla regions. Many
of these are pseudogenes. The number of class I
genes varies between inbred lines of laboratory
mice, probably because of frequent unequal
crossing-over [15, 50]. Of the 65 MHC genes
detected in the blind mouse Spalax ehrenbergi
only three are active [193]. Further class I genes,
other than the transplantation antigen in the H-2
complex, are apparently absent from some rodent
species and are clearly lacking in other mammals.
For example, DNA sequences corresponding to
the Tla gene of the laboratory mouse are detected
in the rat and the golden hamster but not in the
guinea-pig [152]. The human HLA complex consists of more than 20 class I genes, many of them
pseudogenes. The functional transplantation antigens of man have been designated A, Band C.
The Ia antigens of class II are expressed primarily on B lymphocytes and macrophages
[77, 173]. These are heterodimers of two
membrane-anchored, non-covalently bound
chains, a 35-kDa a chain and a 29-kDa ~ chain,
each of which has two extracellular domains. The
domains a2 and ~2 have the structure of Ig homology units (Fig. 6.2). As in the case of class I
6.4 MHC Antigens and ~2-Microglobulins
229
genes, the exon boundaries correspond to domain
boundaries in the proteins. The class II region of
human MHC consists of the subregions HLA-DP,
-DZIDO, -DO and -DR. Each subregion contains a and ~ genes, except DZ, which contains
only a, and DO, which has only ~; in all regions
there are both functional genes and pseudogenes
[87]. The mouse also possesses loci for all four
subclasses, although fewer than in man. Only DP
and DO genes have been detected in the blind
mouse Spalax ehrenbergi and none of the subclasses DZIDO and DR [77].
Like the transplantation antigens of class I, the
class II antigens also show extreme polymorphism. Between 50 and 100 alleles of both classes
may be present in a single mouse population. The
alleles can differ by up to 50 amino acids, mainly
localized in the outer domains, i.e. al and a2 of
the transplantation antigens, and al and ~1 of the
class II antigens. The mechanism leading to this
extreme polymorphism is not completely clear.
Sequence comparisons of man, the chimpanzee
and the mouse show that many of the MHC alleles are very old; this would speak against an
increase in mutation rate. On the other hand,
gene conversion has certainly played a role in the
creation of MHC polymorphism, in addition to
overdominant selection due to a heterozygote
advantage [47, 77, 95,99]. MHC-antigen polymorphism is important for the survival of the species, in so far as the combination of foreign antigen and MHC antigen may correspond by chance
to a particular "self" structure; in such a case
there will be no immune response and the receptor repertoire of the T lymphocyte will have a
"blind spot". The high polymorphism ensures
that this danger does not affect the whole population [78, 87]. In the tamarin Sanguinus oedipus (a
primate) there are only a few class I MHC alleles
and this may well be the cause of the observed
high infectivity of this species [195].
Little can be said at present about the evolution of the MHC because of the absence of
detailed investigations of the lower vertebrates.
Nevertheless, it can be taken as certain that all
vertebrates possess an MHC. The molecularly
well-characterized MHC complex of the chicken
(B complex) has significantly smaller introns, and
is therefore smaller than both human and murine
MHC; it also differs by having much closer linkage of the class I and II genes with each other
and with other genes [63]. The surface of the leukocytes of the frog Xenopus laevis bears both
class I antigen molecules, made up of a polymorphic chain of about 45 kDa and a ~2m-like
antigen; however, the mechanism of this MHC
restriction has not yet been defined. The class III
MHC genes encode components of the complement system and will be discussed in Section 6.6.
The best-characterized MHCs are the murine
H-2 complex and the human HLA complex
[50,87]. The H-2 complex on mouse chromosome 7 extends over 4000 kb. The classical transplantation antigens of class I are encoded in loci
K, D and L. All the genes of this group so far
sequenced contain eight exons corresponding to
the subdivisions of the polypeptide; exon 1 encodes the signal peptide, exons 2-4 encode the
three extracellular domains aI, a2 and a3, exon 5
encodes the transmembrane region and
exons 6-8 code for the small cytoplasmic
domain. The complete polypeptide of 45 kDa,
anchored in the cell membrane, is bound noncovalently via domain a3 to the 12-kDa large
~2microglobulin (~2m). The domain a3 and the
~2m each correspond to one Ig homology unit
(Fig. 6.2). Class I also includes the Oa antigen,
which is found predominantly on Band T lymphocytes, and the Tla antigen, which is found on
the thymocytes; these two molecules are much
more polymorphic than the transplantation antigen and are not involved in the MHC-restricted
recognition by T lymphocytes. In all there are
30-40 class I genes in the mouse, most of which
can be allotted to the Oa and Tla regions. Many
of these are pseudogenes. The number of class I
genes varies between inbred lines of laboratory
mice, probably because of frequent unequal
crossing-over [15, 50]. Of the 65 MHC genes
detected in the blind mouse Spalax ehrenbergi
only three are active [193]. Further class I genes,
other than the transplantation antigen in the H-2
complex, are apparently absent from some rodent
species and are clearly lacking in other mammals.
For example, DNA sequences corresponding to
the Tla gene of the laboratory mouse are detected
in the rat and the golden hamster but not in the
guinea-pig [152]. The human HLA complex consists of more than 20 class I genes, many of them
pseudogenes. The functional transplantation antigens of man have been designated A, Band C.
The Ia antigens of class II are expressed primarily on B lymphocytes and macrophages
[77, 173]. These are heterodimers of two
membrane-anchored, non-covalently bound
chains, a 35-kDa a chain and a 29-kDa ~ chain,
each of which has two extracellular domains. The
domains a2 and ~2 have the structure of Ig homology units (Fig. 6.2). As in the case of class I
6.4 MHC Antigens and ~2-Microglobulins
229
genes, the exon boundaries correspond to domain
boundaries in the proteins. The class II region of
human MHC consists of the subregions HLA-DP,
-DZIDO, -DO and -DR. Each subregion contains a and ~ genes, except DZ, which contains
only a, and DO, which has only ~; in all regions
there are both functional genes and pseudogenes
[87]. The mouse also possesses loci for all four
subclasses, although fewer than in man. Only DP
and DO genes have been detected in the blind
mouse Spalax ehrenbergi and none of the subclasses DZIDO and DR [77].
Like the transplantation antigens of class I, the
class II antigens also show extreme polymorphism. Between 50 and 100 alleles of both classes
may be present in a single mouse population. The
alleles can differ by up to 50 amino acids, mainly
localized in the outer domains, i.e. al and a2 of
the transplantation antigens, and al and ~1 of the
class II antigens. The mechanism leading to this
extreme polymorphism is not completely clear.
Sequence comparisons of man, the chimpanzee
and the mouse show that many of the MHC alleles are very old; this would speak against an
increase in mutation rate. On the other hand,
gene conversion has certainly played a role in the
creation of MHC polymorphism, in addition to
overdominant selection due to a heterozygote
advantage [47, 77, 95,99]. MHC-antigen polymorphism is important for the survival of the species, in so far as the combination of foreign antigen and MHC antigen may correspond by chance
to a particular "self" structure; in such a case
there will be no immune response and the receptor repertoire of the T lymphocyte will have a
"blind spot". The high polymorphism ensures
that this danger does not affect the whole population [78, 87]. In the tamarin Sanguinus oedipus (a
primate) there are only a few class I MHC alleles
and this may well be the cause of the observed
high infectivity of this species [195].
Little can be said at present about the evolution of the MHC because of the absence of
detailed investigations of the lower vertebrates.
Nevertheless, it can be taken as certain that all
vertebrates possess an MHC. The molecularly
well-characterized MHC complex of the chicken
(B complex) has significantly smaller introns, and
is therefore smaller than both human and murine
MHC; it also differs by having much closer linkage of the class I and II genes with each other
and with other genes [63]. The surface of the leukocytes of the frog Xenopus laevis bears both
class I antigen molecules, made up of a polymorphic chain of about 45 kDa and a ~2m-like